Disorder in the regularity of the systolic motion of the heart is called arrhythmia. Conditions of arrhythmia include one in which the cardiac output extremely decreases to induce ischemia in the whole body, one which invokes a danger of aggravating to serious arrhythmia, and one which has a strong subjective symptom. Treatment of arrhythmia is mainly by chemotherapy, and many anti-arrhythmic drugs have been clinically applied. Heretofore, the following proposals have been made with regard to anti-arrhythmic drugs.
Japanese Laid-Open Patent Publication No. 42815/1974 discloses a method of producing a compound having anti-arrhythmic activity which is represented by the formula ##STR2## wherein X.sup.- is an anion such as a halide, sulfate, methyl sulfate, alkylsulfonate (where the alkyl moiety has 1 to 4 carbon atoms), or
ortho-, meta- or pyrro-phosphate ion, which comprises contacting a tertiary amine represented by the following formula ##STR3## wherein R represents methyl and R' represents methyl or isopropyl, with a compound represented by EQU (alkyl)X PA1 wherein one of the alkyl and R' is methyl and the other is isopropyl, and X is as defined. PA1 X represents C or N; and PA1 A represents phenyl or phenyl substituted by lower alkyl, lower alkoxy, lower thioalkoxy, halogen or trifluoromethyl; 2-, 3- or 4-pyridinyl or 2-, 3- or 4-pyridinyl substituted by lower alkyl, lower alkoxy or halogen; 2-, 4- or 5-pyrimidinyl or 2-, 4- or 5-pyrimidinyl substituted by lower alkyl, lower alkoxy or halogen; 2-pyrazinyl or 2-pyrazinyl substituted by lower alkyl, lower alkoxy or halogen; 2- or 3-thienyl or 2- or 3-thienyl substituted by lower alkyl or halogen; 2- or 3-furanyl or 2- or 3-furanyl substituted by lower alkyl or halogen; or 2- or 5-thiazolyl or 2- or 5-thiazolyl substituted by lower alkyl or halogen, PA1 or A represents a group selected from the class consisting of lower alkenyl, lower acyl, lower acylvinyl and alpha,alpha-di-lower alkylbenzyl, and B is hydrogen, lower acyloxy, lower alkoxy or benzoyloxy; PA1 R.sup.1 is hydrogen, lower alkyl, lower alkoxy, halogen, amino, nitro or lower alkylsulfamoyl; PA1 R.sup.2 is hydrogen, hydroxyl or lower alkyl; PA1 R.sup.3 is hydrogen, alkyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, lower acyl-lower alkyl, ethylenedioxy lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, benzyl, ##STR11## R.sup.4 is alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, hydroxyalkyl, cycloalkyl, benzyl, phenethyl, cyclohexyloxy, 2-bicyclo[2.2.1]heptanyl, adamantyl, piperidino which may be substituted, or 2-tetrahydrofuranylmethyl, or R.sup.3 and R.sup.4, taken together with the nitrogen atom to which they are bonded may form a 4- to 8-membered ring represented by the following formula ##STR12## R.sup.5 -R.sup.10, R.sup.13 -R.sup.27, R.sup.29 -R.sup.32 and R.sup.34 -R.sup.49 are identical or different, and each represents hydrogen or lower alkyl; PA1 R.sup.11 is hydrogen, hydroxyl, lower alkoxy, lower acyloxy or lower alkyl; PA1 R.sup.12 is hydrogen, lower alkyl, lower acyl or benzoyl; PA1 R.sup.28 and R.sup.50 are identical or different and each represents hydrogen, phenyl or lower alkyl; PA1 R.sup.33 is hydrogen, lower alkyl or lower alkoxy; PA1 R.sup.51 -R.sup.53 are identical or different and each represents lower alkyl; PA1 X and Y are identical or different and each represents lower alkylene; PA1 Z is methylene, imino, oxygen or sulfur; PA1 R.sup.05 and R.sup.06 are substituents on X, Y or Z, and, independently from each other, represent hydrogen, lower alkyl, hydroxy-lower alkyl, lower alkoxy, cyclohexyl, hydroxyl, carboxyl, carbamoyl, lower alkoxycarbonyl, lower alkylsulfonamide, di-lower alkylcarbamoyl, lower alkylamide, aryl which may be substituted, benzyl which may be substituted, benzoyl which may be substituted, or heteroaryl which may be substituted, or R.sup.05 and R.sup.06, bonded to each other, may form oxo (.dbd.O), lower alkylene, ethylenedioxy or --CONHCH.sub.2 N(C.sub.6 H.sub.5)--, or when they are present on adjacent carbon atoms, they may form a benzene ring together with the carbon atoms; PA1 n is a number of 0, 1, 2, 3 or 4; and PA1 m is 3 or 4 (the plurality of R.sup.34 and R.sup.35 groups may be identical or different); provided that when R.sup.3 and R.sup.4 form the above 4- to 8-membered ring together with the nitrogen atom to which they are bonded, A and B together represent a group of formula (a), (c), (h) or (p), or A is lower acyl and B is lower alkoxy, or A and B together represent the group of formula (a), and when R.sup.3 and R.sup.4 form a 6-membered ring together with the nitrogen atom to which they are bonded, it is not a 6-membered ring in which the fourth position counted from the nitrogen atom bonded to CH.sub.2 --.sub.n as the first position is lower alkylimino, phenylimino, 2-pyridinylimino, lower alkylmethylene or benzyl. Compounds represented by formula (1) can be divided, for the sake of convenience, into two groups of compounds represented by the following formulae (1)-1 and (1)-2. ##STR13## wherein A, B, R.sup.1, R.sup.2 and n are the same as defined in formula (1); PA1 R.sup.03 is hydrogen, alkyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, lower acyl-lower alkyl, ethylenedioxy-lower alkyl, lower alkenyl, lower alkynyl, cyloalkyl, phenyl, benzyl, ##STR14## R.sup.04 is alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, hydroxyalkyl, cycloalkyl, benzyl, phenethyl, cyclohexyloxy, 2-bicyclo[2.2.1]heptanyl, adamantyl, piperidino which may be substituted, or 2-tetrahydrofuranylmethyl; and, PA1 R.sup.51, R.sup.52 and R.sup.53 are as defined as in formula (1); PA1 R.sup.1, R.sup.2, n, R.sup.05, R.sup.o6, X, Y and Z are as defined in formula (1); PA1 provided that when A.sup.0 and B.sup.0 together represent the group (a) and the ring formed by N, X, Y and Z is a 6-membered ring, it is not a 6-membered ring in which the fourth position counted from the nitrogen atom bonded to --CH.sub.2 --.sub.n as the first position is lower alkylimino, phenylimino, 2-pyridinylimino, lower alkylmethylene or benzyl; and acid addition salts or quaternary ammonium salts
Japanese Patent Publication No. 9952/1986 discloses a benzo(b)furan derivative represented by the following formula and its salt ##STR4## wherein R.sub.1 and R.sub.2, independently from each other, represent alkyl, or form a 4- to 8-membered saturated heterocycle which may contain an oxygen or nitrogen atom as a second hetero atom together with the nitrogen atom to which they are bonded, the nitrogen atom may be substituted by phenyl which may be substituted by halogen, trifluoromethyl, alkyl or alkoxy, and n is 2 or 3.
This patent document describes that the above compounds have anti-arrhythmic activity as well as analgesic activity.
Japanese Patent Publication No. 14538/1987 discloses the use of a quaternary ammonium salt of a phenylalkylamine represented by the following formula ##STR5## wherein n is 1 or 2; R.sup.1 represents H or C.sub.1 -C.sub.2 alkyl; R.sup.2 represents H or C.sub.1 -C.sub.3 alkyl; R represents C.sub.1 -C.sub.4 alkyl or phenyl-C.sub.1 -C.sub.4 alkyl; R.sup.4 represents C.sub.1 -C.sub.8 alkyl; R.sup.5 represents C.sub.1 -C.sub.10 alkyl; R.sup.6 and R.sup.7, independently from each other, represent H, OH, halogen, NO.sub.2, C.sub.1 -C.sub.3 alkoxy or C.sub.1 -C.sub.3 alkyl (with the proviso that at least one of R.sup.6 and R.sup.7 is H, and when n is 1 and both R.sup.6 and R.sup.7 are NO.sub.2, R.sup.5 is C.sub.6 -C.sub.10 alkyl); and X represents a phamaceutically acceptable anion,
as an anti-arrhythmic agent.
Japanese Laid-Open Patent Publication 252783/1987 discloses compounds of the following formula ##STR6## wherein Het is selected from the following groups ##STR7## n is an integer of 2 to 5; . . . represents a single or double bond;
or pharmaceutically acceptable acid addition salts thereof (excepting compounds of the above formula in which X is N, Het is ##STR8## and A is phenyl or substituted phenyl). This patent document describes that these compounds have a pharmacological efficacy as antipsychotic agents.
Anti-arrhythmic agents are classified by the differences in their action on the potential difference between the inside and outside of the myocardial cell membrane, which differences occur when the antiarrhythmic agents bind to various ion channels of the myocardial cell membrane to change ion's permeability to these channels. Vaughan Williams classified antiarrhythmic agents as classes I, II, III and IV on the basis of their electrophysiological characteristics, and this classification has generally been used.
A series of changes in membrane potential which occur when a myocardial cell in a stationary state is stimulated and gets excited and returns to the stationary state are called action potential, and the time required from the occurrence of the action potential until the stationary state is restored is known as action potential duration (APD for short).
The cardiac muscles cannot be re-excited immediately after, or during, the occurrence of an action potential. This is called refractoriness, and the time during which even a great stimulation cannot induce excitation is called the effective refractory period, or ERP. This refractory period has closely to do with the duration of the action potential.
Anti-arrhythmic agents belonging to class I are a sodium channel blocker, and are sub-classified into Ia, Ib and Ic by the mechanism of their action on APD and ERP. Ia denotes a drug which prolongs APD and ERP and includes, for example, quinidine, procainamide and disopyramide. Ib is a drug which shortens APD and ERP and includes, for example, lidocaine and mexiletine. Ic is a drug which maintains APD and ERP unchangeable, and includes, for example, flecainide.
Anti-arrhythmic agents belonging to class II are sympathiotonia inhibitors which correspond to many beta-blockers. Anti-arrhythmic agents of class III are drugs which markedly prolong APD and ERP, and include, for example, amiodarone, bretylium, and sotalol, but have not yet been marketed in Japan. Anti-arrhythmic agents belonging to class IV are calcium channel blockers and include, for example, verapamil, diltiazem and nicardipine.
The excitation of the heart is successively transmitted through a stimulation transmitting system ranging from the stinoatrial node to the Purkinje fiber, and contracts the atrium and ventricle. Swinging of the excitation transmission as a result of the stimulation transmitting system getting out of order is called reentry. If the excitation swinging ends through one turn, extrasystole occurs, and if it continues, tachycardia occurs. If reentry occurs here and there simultaneously, flutter and fibrillation result.
It is suggested that drugs which markedly prolong APD and ERP can inhibit or prevent such ventricular extrasystole, tachycardia, ventricular fibrillation, etc. Annual Reports in Medicinal Chemistry, H. J. Hess ed., Academic Press, New York, N.Y.; see General Review of J. Thomis et al. in Vol. 18, Chapter 11 (1983).]
The anti-arrhythmic agents of class III correspond to these drugs, and are useful for treating and preventing ventricular arrhythmia which are serious or on which the other class of drugs are ineffective, but the research and development of these drugs fall behind the research and development of the anti-arrhythmic agents of classes I, II and IV, particularly class I.
Clofilium [Japanese Laid-Open Patent Publication No. 95520/1979, Japanese Patent Publication No. 14538/1987, U.S. patent application Ser. No. 861789 (1977) now abandoned, European Patent Application No. 2604 (1979), melperone, meobentine, pirmentol, and the above-mentioned amiodarone, bretylium, and sotalol are among known anti-arrhythmic agents of class III. Some of them have strong class I activity, and it is only the last three compounds which are actually applied clinically. The reason which can be cited is that many of these drugs have strong toxicity and poor transport to tissues and concurrently inhibit the function of the heart in effective concentrations, and may induce undesirable central nervous side-effects. Furthermore, these compounds are not orally administrable because of their properties, and this prevents their clinical application. The aforesaid drugs now clinically applied more or less entail the above various problems.
On the other hand, psychotic diseases such as mania, depression, schizophrenia, delirium, dementia and anxiety are widely treated by chemotherapy using various psychotropic drugs. It is expected to develop drugs having higher safety and duration and being easier to use, or psychotropic drugs having a new action mechanism, a broad action spectrum and a novel chemical structure.
It is an object of this invention to provide novel amines, acid addition salts and quaternary ammonium salts thereof.
Another object of this invention is to provide a novel and useful class III anti-arrhythmic agents comprising the above compounds of this invention which have very favorable biological activity, prolong APD and ERP markedly and exhibit anti-arrhythmic activity in various arrhythmic models.
Still another object of this invention is to provide novel and useful drugs for central nervous system and pyschotropic drugs, such as anti-depressants, antianxiety agents, sedatives and anti-dementia agents.
Further objects of the invention along with its advantages will become apparent from the following description.